Abstract The overall goal of this research proposal is to prospectively examine the impact of three modern antiretroviral therapy (ART) treatment strategies on the progression of atherosclerosis in treatment-nave individuals with human immunodeficiency virus (HIV) infection. The studies proposed will examine and quantify the contributions of ART, cardiovascular disease (CVD) risk factors, immune activation and inflammation on arterial injury and atherosclerosis progression in HIV-infected individuals. The co-principal investigators are an infectious disease specialist and a cardiologist with expertise in the investigation of CVD risk in patients with HIV. They have assembled a multidisciplinary team of investigators that includes two experts in the treatment of HIV, two cardiologists with expertise in atherosclerosis imaging and lipids, an endocrinologist, and an immunologist, and a cardiovascular basic scientist, who, in collaboration with the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group AIDS Clinical Trials Group, will conduct a prospective substudy of A5257, A Comparative Study of Three Compact, Non-Nucleoside Reverse Transcriptase Inhibitor Sparing Antiretroviral Regimens for the Treatment Naive HIV-1 Infected Volunteers. A5257 is a prospective, randomized clinical trial (RCT) of ART efficacy. Embedding analyses of structural and functional markers of arterial injury and their determinants in a prospective, randomized clinical trial within the ACTG is an efficient and cost-effective approach to understanding the contributions of traditional and HIV-related factors to atherosclerosis progression in individuals with HIV. The proposal includes the following clinical and mechanistic aims: AIM 1 (Clinical): To examine the effects of three contemporary initial ART treatment strategies on atherosclerosis progression over three years. AIM 2 (Mechanistic and clinical): To examine the magnitude and time course of the effects of three contemporary initial ART treatment strategies on endothelial function during the first year of therapy. AIM 3 (Mechanistic): To examine the effects of ART-related metabolic changes on endothelial function and atherosclerosis progression. AIM 4 (Mechanistic): To examine the effects of ART-related changes in immune function and inflammation on endothelial function and atherosclerosis progression.